Insulin resistant individuals become diabetic when beta-cells lose their normal ability to respond to glucose and to compensate for the pre- existing insulin resistance. To identify the beta-cell defect that results in NIDDM, we plan to characterize in rats the molecular, metabolic and physiologic components of the normal beta-cell compensatory response induced 1) by hyperglycemic clamping, 2) by dexamethasone treatment, and 3) by obesity and compare these with beta-cells of various rat models that cannot compensate these same factors (eg ZDF-drt rats, GK rats, Zucker fa/fa rats and rats after subdiabetic streptozotocin treatment). Functional measurement include 1) insulin responses to 5, 10, 20 mM glucose, glyceraldehyde and monomethyl succinate to localize a block, 2) measurements of glucose transport metabolism, utilization, oxidation and glucokinase activity further to localize such a block, 3) quantitation of beta-cell proinsulin, GLUT-2, glucokinase and G protein alpha mRNA to determine if expression of key proteins is impaired, 4) morphometric analysis of percent GLUT-2 and glucokinase containing beta- cell mass by immunocytochemistry, 5) beta-cell volume to determine if expansion of the beta-cell mass impaired and 6) morphometric assessment of mitochondrial integrity by electronmicroscopy. Longitudinal measurements will be made a weekly intervals from six weeks before and until six weeks after the onset of diabetes. The hope is to find a consistent difference in various diabetic rat models of seemingly crucial component of the normal compensatory response that might point to the pathogenic locus.